Schwann cells (SCs) and oligodendrocytes are important glial cells that provide myelin sheathing around the axons of neurons. Schwann cells provide myelin sheathing around axons in the peripheral nervous system and oligodendrocytes provide myelin sheathing around axons in the central nervous system.
During peripheral nerve myelination in the early postnatal period, the matching of SC and axon numbers is regulated by SC apoptosis, resulting in the mature 1:1 relationship between axons and myelinating SCs. After this period of SC proliferation and myelination, SCs are generally inactive. However, upon injury SCs will demyelinate around the injured axon and reenter the cell cycle thereby remyelinating the regenerated axon. Accordingly, it is believed that SCs receive survival and differentiation signals from growing axons during peripheral nerve development and regeneration, based on studies of SCs following nerve transection. It has also been shown that oligodendrocytes will remyelinate after pathological lesions to the central nervous system.
Myelin producing cells thus play an important role in the development, function, and regeneration of nerves. The implications of this from a therapeutic perspective have been addressed by Levi et al. in J. Neurosci., 1994, 14(3):1309, where the authors discuss the potential for cellular prostheses comprising human SCs which could be transplanted into areas of damaged spinal cord. Accordingly, these authors outline the need for SC mitogens which can be used to allow full differentiation of these cells ex vivo. The published patent application, WO 94/00140, describes the use of various factors for stimulating mitogenesis of glial cells including SCs. Others have demonstrated that neuregulin is a potent mitogen for human SCs in vitro.
Agents that promote growth and survival of myelin producing cells can be useful for a variety of therapeutic purposes. Diseases and conditions of the nervous system that result from the deterioration of, or damage to, the myelin sheathing generated by myelin producing cells are numerous. Myelin may be lost as a primary event due to direct damage to the myelin or as a secondary event as a result of damage to axons and neurons. Primary events include neurodegenerative diseases such as Multiple Sclerosis, human immunodeficiency MS-associated myelopathy, transverse myelopathy/myelitis, progressive multi focal leukoencepholopathy, central pontine myelinolysis and lesions to the myelin sheathing (as described below for secondary events). Secondary events include a great variety of lesions to the axons or neurons caused by physical injury, ischemia diseases, malignant diseases, infectious diseases (such has HIV, Lyme disease, tuberculosis, syphilis, or herpes), degenerative diseases (such as Parkinson's, Alzheimer's, Huntington's, ALS, optic neuritis, postinfectious encephalomyelitis, adrenoleukodystrophy and adrenomyeloneuropathy), nutritional diseases/disorders (such as folic acid and Vitamin B12 deficiency, Wernicke disease), systemic diseases (such as diabetes, systemic lupus erthematosis, carcinoma), and toxic substances (such as alcohol, lead, ethidium bromide); and iatrogenic processes such as drug interactions, radiation treatment or neurosurgery.
Lysophosphatidic acid (LPA) is a bioactive lipid with properties of an extracellular growth factor for many cell lines. However, the relationship between LPA and complex tissues such as the developing nervous system has been unclear.
It has now been surprisingly found that agents that stimulate LPA receptors, such as LPA, have the desirable property of promoting the survival of myelin producing cells, in particular SCs and oligodendrocytes.